The Japanese journal of antibiotics最新文献

Severely ill patients are frequently at risk of developing fungal infection. Itraconazole (ITCZ), a triazole antifungal agent, is used for the treatment of candidiasis, aspergillosis, cryptococcosis. Correlation of pharmacokinetic and pharmacodynamic (PK-PD) parameters with the in vivo bactericidal action of antimicrobial agents has progressed markedly in recent years. However, the optimal dosage of antifungal agents based on PK-PD properties has not been clearly established. In this study, we performed a population pharmacokinetic analysis of ITCZ after infusion or oral administration of ITCZ in Japanese 51 patients with fungal infections. The population pharmacokinetic analysis was performed using NONMEM software. The population mean clearance (CL; liter/h) was estimated as 5.15-0.0673 x(Age-62) L/h, the population mean volume of distribution (V; liter) was determined as 878L and the bioavailability (F) was determined as 0.665.

As a special drug use investigation, we monitored and assessed trends in antibacterial activity of clavulanic acid/amoxicillin (1:14) (hereafter, "CVA/AMPC (1:14)") and other antimicrobial agents for clinical isolates from pediatric patients with otitis media or respiratory, skin, and urinary tract infections. Against Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis isolated and identified from otorrhea, epipharynx and rhinorrhea of pediatric patients with otitis media, the MIC90s of CVA/AMPC (1:14) in five years between 2006-2010 were 1 microg/mL for S. pneumoniae and 8 microg/mL for H. influenzae and 0.25-0.5microg/mL for M catarrhalis. The changes of MIC90s of CVA/AMPC (1:14) for penicillin-resistant S. pneumoniae (PRSP) and beta-lactamase non-producing H. influenzae were two times, and no decrease in drug susceptibility was found in the period of the present investigation. In addition, the MIC changes of other antimicrobial agents for these three organisms were approximately two to four times as well. Against organisms isolated and identified from pus, sputum, pharynx, skin and urine of pediatric patients with respiratory, skin, and urinary tract infections, the MIC90s of CVA/AMPC (1:14) in four years between 2008-2011 were 1 microg/mL for S. pneumoniae, < or =0.06microg/mL for penicillin susceptible S. pneumoniae (PSSP) without any change, 0.5-1 microg/mL for penicillin intermediate resistant S. pneumoniae (PISP) with a twofold change and 1 microg/mL for PRSP with no change. The MIC90s of CVA/AMPC (1:14) were 2-8 microg/mL for S. aureus with a fourfold change, 2 microg/mL for methicillin-sensitive S. aureus without any change, 4-8 microg/mL for H. influenzae with a twofold change. Against beta-lactamase non-producing H. influenzae, MIC90s of CVA/AMPC (1:14) were 1 microg/mL for beta-lactamase negative ampicillin susceptible (BLNAS), 8 microg/mL for beta-lactamase negative ampicillin resistant (BLNAR), showing no change. Neither Streptococcus pyogenes or Klebsiella pneumoniae demonstrated any change and M. catarrhalis and Escherichia coli showed twofold changes of MIC90s of CVA/AMPC (1: 14). In the present investigation conducted to monitor annual changes in antibacterial activity intended for pediatric patients with otitis media or other infections, there was no significant change in antibacterial activity of CVA/AMPC (1: 14).

We assessed the safety and pharmacokinetics of arbekacin sulfate (ABK, brand name: Habekacin injection) in single and 7-day multiple administration of ABK 400 and 600 mg as potency to healthy male volunteers. In the single administration of ABK 400 and 600 mg (over 30 min, drip infusion), C(max) values were 41.0 +/- 3.6 microg/mL and 63.0 +/- 9.9 microg/mL, respectively. Serum ABK concentrations at 60 min (C(peak)) after the start of administration were 23.2 +/- 2.9 microg/mL and 38.5 +/- 3.3 microg/mL, respectively, and the mean serum ABK concentrations at 24 hr (C(trough)) after the start of administration were less than 0.4 microg/mL (LOQ: limited of quantitation). C(max), Cpeak and AUC(0-infinity) were increased with doses, and t1/2, CL(tot), CL(r) V(ss) and urinary excretion were comparable at both doses. In the multiple administration of ABK 400 and 600 mg (over 30 min, drip infusion) once a day for 7 days, C(max0, C(peak) and AUC(0-infinity) were comparable from the 1st day through to 7th day and increased with doses. After the administration, the serum ABK concentrations were decreased with time, and the means of C(trough) were 0.4 microg/mL (LOQ) -0.5 microg/mL, which showed ABK has no tendency toward accumulation. In addition, t1/2, CL(tot), CL(r) V(ss) and urinary excretion were constant throughout administration days at either dose, and CL(tot) containing CL(r) was not decreased. There were no notable changes in the functions of the kidney, auditory organs, etc. Based on the above-mentioned results, when ABK 400 or 600 mg was intravenously administered over 30 min once or once a day for 7 days to the healthy male volunteers with normal renal clearance, it is suggested there were no problems in terms of safety, and C(max) were 36.7-54.1 and 44.2-78.5 microg/mL, respectively. In addition, C(trough) was 0.5 microg/mL or lower at either doses and ABK was not accumulated in multiple administration of ABK. ABK was, therefore, expected to have good safety profile and favorable pharmacokinetics.

The growing number of infection caused by extended-spectrum beta-lactamase (ESBL) producing pathogens has prompted a more rational use of available antibiotics because of the paucity of new, effective agents. Flomoxef (FMOX) is one of the beta-lactam antibiotic which is stable against beta-lactamase. In this study, the antibacterial activity of FMOX was investigated, and Monte Carlo Simulation was conducted to determine the appropriate dosing regimens of FMOX based on the probability of target attainment (TA%) at the critical drug exposure metric of time that drug concentrations remain above 40% (showing bacteriostatic effect) or 70% (showing bactericidal effect) of time during which plasma concentration above minimum inhibitory concentration (MIC) of the drug (T(>MIC)) against the ESBL producing Enterobacteriaceae. The effective regimens to achieve 80% of TA% at 70% of T(>MIC) were 1 g every 8 hours with 2-4 hours infusion, and 1 g every 6 hours with 1-4 hours infusion. Moreover, all the tested regimens were effective to achieve 80% of TA% at 40% of T(>MIC). These results of pharmacokinetics/ pharmacodynamics (PK/PD) modeling showed the potential efficacy of FMOX against bacterial infections caused by ESBL producing Enterobacteriaceae.

This study was performed to elucidate the relationship between antimicrobial use density (AUD) and Clostridium difficile infection (CDI) manifesting as antimicrobial-associated diarrhea (AAD) in hospital wards during a 4-year period. Case definition of CDI was an adult exhibiting AAD with a daily stool frequency of three or more, arising at least 48 hours after ward admission, and fecal samples testing positive for toxin (A and/or B). Metronidazole or vancomycin was orally administered as treatment. AUDs were calculated for a total of 21 antimicrobials in a span of 48 months and nine wards. We included the average value of AUDs, representing two succeeding months of sample submission into the sample information. We also entered data on the 2-year division and intensified contact precaution for statistical analysis. Of a total of 463 cases, 95 (20.5%) were CDI-positive. Multivariate regression analysis showed odds ratios [OR] of 1.739 (95% confidence interval [CI] of 1.050 - 2.881, P = 0.032) and 1.598 (95% CI of 1.006 -2.539, P = 0.047) for clindamycin and piperacillin, respectively in AUD. Thus increased ward AUDs of clindamycin and piperacillin may run the risk of CDI.

Patients with nursing and health care-associated pneumonia (NHCAP) include those at risk for aspiration or those who have difficulties to take pills. We conducted a prospective study to examine the efficacy and safety of moxifloxacin (MFLX) administration through an enteral feeding tube by a simple suspension method in patients with NHCAP receiving long-term care at the hospital. The study was performed in subjects meeting the definition of NHCAP according to the Japanese Respiratory Society amongst patients with pneumonia who were fed by a feeding tube under long-term care at Makita General Hospital during the period from Dec. 2010 to Oct. 2011. A dose of 400 mg MFLX was administered once daily for three consecutive days, as a rule, through a gastrostomy or nasogastric feeding tube by a simple suspension method. The primary endpoint was a test of cure (TOC) 7 days after the last administration. Sixteen patients were included in the analysis of the study. As the patient background, 11 were assessed as long-term care level 5, 5 were not receiving care, and the Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score was 4 in all patients. Twelve (75%) had experience of aspiration while 4 (25%) had none, and all had some underlying diseases (complications). The severity of pneumonia according to the A-DROP scoring system was mild in 1 patient (6%), moderate in 14 patients (88%) and severe in 1 patient (6%). A test of cure 7 days after the last administration, which was the primary endpoint, showed an efficacy rate of 81.3% (13/16 patients), while the efficacy evaluation 3 days after administration, which was an endpoint for early phase drug efficacy, showed that the drug was effective in all patients (100%; 16/16 patients). Neither adverse drug reactions nor abnormal laboratory findings were observed. MFLX administration through an enteral feeding tube by a simple suspension method was shown to be as highly effective as injection in patients with NHCAP having eating and swallowing disorders, indicating its potential to become an alternative option to conventional intravenous injection therapy.

We conducted a study assess the bactericidal activity of sitafloxacin (STFX) against Streptococcus pneumoniae isolates recovered from respiratory infections including penicillin-resistant (PRSP) isolates, macrolide resistant isolates possessing mefA and ermB resistance genes and quinolone resistance isolates with mutations in gyrA or gyrA and parC. Each isolate tested was grown in hemosupplemented Mueller-Hinton broth and adjusted to approximately 10(5) CFU/ mL. Isolates were than exposed to a Cmax antimicrobial blood level that would be attained with routine antimicrobial administration and an antimicrobial level that would be expected 4 hours post-Cmax (Cmax 4hr). Bactericidal activity was measured for up to 8 hours. Excluding a subset of S. pneumoniae isolates with mutations in the quinolone resistance determining region (QRDR), all quinolones showed bactericidal activity at Cmax and Cmax 4 hr antimicrobial concentrations for up to 8 hours. Against S. pneumoniae isolates with either gyrA or gyrA and parC mutations, bactericidal activity of STFX was shown for up to 4 to 8 hours following Cmax based on a limit of detection of < 1.3 log CFU/mL. Garenoxacin (GRNX) did not showed bactericidal activity below the limit of detection for up to 8 hours with exposure to Cmax and no bactericidal activity was seen with levofloxacin. When all quinolones tested where adjusted to concentrations corresponding to their MICs, STFX showed the most rapid bactericidal activity against PRSP. This rapid bactericidal activity in PRSP is a key to the effectiveness of STFX. Our findings show that beyond inhibition of bacterial replication by blocking their DNA replication pathway and synthesis of proteins, STFX demonstrated characteristics contributing to greater bactericidal activity compared to GRNX. In conclusion, of the newer quinolones, STFX showed the strongest bactericidal activity against S. pneumoniae isolates with mutations in the QRDR which indicates that it may show the most effective clinical utility among the quinolones in respiratory infections.